Clinical Acquired Resistance to KRASG12C Inhibition through a novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation

Mutant-selective KRAS(G12C) inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRAS(G12C)-mutant cancers, including non-small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRAS(G12C) inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with KRAS(G12C) NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (KRAS, NRAS, BRAF, MAP2K1), all of which converge to reactivate RAS-MAPK signaling. Notably, a novel KRAS(Y96D) mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein-drug interactions and confers resistance to these inhibitors in engineered and patient-derived KRAS(G12C) cancer models. Interestingly, a novel, functionally distinct tricomplex KRAS(G12C) active-state inhibitor RM-018 retained the ability to bind and inhibit KRAS(G12C/Y96D) and could overcome resistance. SIGNIFICANCE: In one of the first reports of clinical acquired resistance to KRAS(G12C) inhibitors, our data suggest polyclonal RAS-MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRAS(G12C) inhibitor.

Automated summary

This study described a patient with KRAS(G12C) non-small cell lung cancer who developed polyclonal acquired resistance to MRTX849 treatment. The research identified 10 heterogeneous resistance alterations that converged to reactivate the RAS-MAPK signaling pathway. Additionally, a novel KRAS(Y96D) mutation affecting key protein-drug interactions and driving resistance was discovered.